Genetic Variant NM_012435.3:c.1415G>A (chr19-422351-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012435.3(SHC2):c.1415G>A(p.Arg472Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,607,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SHC2
NM_012435.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

Publications

0 publications found

Variant links:

Genes affected

SHC2 (HGNC:29869): (SHC adaptor protein 2) Predicted to enable receptor tyrosine kinase binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in cytosol. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22156122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHC2	NM_012435.3 link	c.1415G>A	p.Arg472Gln	missense_variant	Exon 11 of 13	ENST00000264554.11	NP_036567.2	P98077

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHC2	ENST00000264554.11 link	c.1415G>A	p.Arg472Gln	missense_variant	Exon 11 of 13	1	NM_012435.3	ENSP00000264554.4	P98077
SHC2	ENST00000588376.5 link	n.478G>A		non_coding_transcript_exon_variant	Exon 1 of 3	1
SHC2	ENST00000590170.3 link	n.352G>A		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000465764.3	K7EKS8

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000392

AC:

AN:

229492

AF XY:

0.0000237

show subpopulations

Gnomad AFR exome

AF:

0.000233

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000589

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000979

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1454802

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

723210

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33346

American (AMR)

AF:

0.0000227

AC:

AN:

44046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39356

South Asian (SAS)

AF:

0.000200

AC:

AN:

85184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1109526

Other (OTH)

AF:

0.0000167

AC:

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000260

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000250

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1415G>A (p.R472Q) alteration is located in exon 11 (coding exon 11) of the SHC2 gene. This alteration results from a G to A substitution at nucleotide position 1415, causing the arginine (R) at amino acid position 472 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.2

PhyloP100

3.4

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.0

REVEL

Benign

0.14

Sift

Benign

0.17

Sift4G

Benign

0.36

Polyphen

0.48

Vest4

0.30

MVP

0.84

MPC

0.35

ClinPred

0.51

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over